Project Summary/Abstract Caffeine is a widely consumed drug that may cause or exacerbate anxiety, insomnia, panic attacks, hypertension, urinary incontinence, gastrointestinal disturbance, and problems in pregnancy. Although caffeine is not generally associated with life-threatening health risks, caffeine has been the subject of recent FDA regulatory concerns. Some people become clinically dependent on caffeine and are unable to cut back or quit caffeine use despite wanting to for medical reasons. Caffeine may be both an important predictor and a determinant of vulnerability to substance abuse. Co-ingesting caffeine and alcohol has been implicated in increases in reckless behavior and alcohol-related injury. A series of three human laboratory studies and one epidemiological survey study will extend previous research investigating the clinical pharmacology of caffeine as a model system for understanding substance use disorders. Each of the studies is a direct extension of prior research conducted on this grant project. One laboratory study will investigate caffeine choice as a predictor of abuse potential of a pharmacologically diverse group of drugs including nicotine and hydrocodone, which are of particular concern as abused substances. A second laboratory study will investigate the effect of caffeine maintenance on the abuse liability (including measures of subjective effects and drug reinforcement) of nicotine delivered via electronic cigarettes (e-cigarettes) to never-smokers. The third laboratory study will determine if co-consumption of caffeine with alcohol increases risk-taking on behavioral measures of monetary and HIV risk decisions. All three laboratory studies may have important public education and regulatory implications. For example, findings indicating that caffeine is a predictor or determinant of vulnerability to substance use disorders for drugs such as opioids or nicotine would be relevant to medical practice and public policy. The epidemiological survey study will determine, in a general population sample, the prevalence, extent of functional impairment, and correlates of Caffeine Use Disorder, which was recently included in DSM-5 as a condition for further study. An accurate prevalence estimate and knowledge of demographic correlates may be important in developing treatment interventions, while assessment of clinically meaningful impairment is critical to assessing the validity of the diagnosis. The survey results may also encourage the inclusion of caffeine in important larger national epidemiological surveys of drug use and health that currently exclude caffeine. In addition to the specific contributions of each of the studies, the investigation of caffeine as a model system for understanding substance dependence should have broad relevance to the development of prevention and treatment strategies for substance abuse and dependence. Data from this project will contribute to a scientific understanding of drug abuse and will ultimately contribute to the development of improved prevention and treatment procedures.